The age-associated decline in circulating gonadal hormones in both men and women may have considerable impact on brain aging given the widespread and critical functions that hormones such as estrogen and progesterone regulate, ranging from reproductive function to neuroprotection. Thus, it is predicted that age-associated neuronal dysfunction may result from, or be contributed by, the loss of critical maintenance and neuroprotective factors, the hormones. In this proposal, we will evaluate the mechanisms by which the gonadal hormone, progesterone, protects neurons from the cellular pathology associated with age and age-associated diseases like Alzheimer's Disease (AD). We have recently shown that progesterone activates two signaling pathways relevant to neuroprotection, the Mitogen-Activated Protein Kinase (MAPK) pathway and Phosphotidylinositol-3 Kinase (PI-3K)/Akt pathway. Using an in vitro model of aging, we will identify if discrete signaling proteins within the MAPK and PI-3K pathways are critical for progesterone's protective actions. Since neurotrophins such as BDNF and NGF have well described neuroprotective functions in the brain, we will evaluate if progesterone regulates neurotrophin expression, and if such regulation is necessary for progesterone's neuroprotective actions. Progesterone (particularly its metabolites) also alters GABAA receptor function, whose activity can influence cell survival. Our preliminary data show that progesterone, unlike its metabolite allopregnanolone, inhibits the GABAA receptor. Since age-related neuronal dysfunction may, in part, result from chronic stimulation of the GABAA receptor (since GABA levels are elevated with age), we propose that progesterone's ability to inhibit the GABAA receptor is a protective mechanism, and that such effects are distinct from its 5alpha-reduced metabolite. Furthermore, our preliminary data also suggest that progesterone's ability to regulate GABAA receptor function occurs via cell signaling. As such, we will identify if progesterone affords neuroprotection via the GABAA receptor, in a MAPK and/or PI-3K dependent manner. We will also correlate the expression and phosphorylation states of signaling proteins relevant to neuroprotection (such as ERK and Akt) with cognitive function in behaviorally-characterized, aged mice. Collectively, these studies will not only advance our understanding of the neurobiology of hormones, but may lead to new and important strategies in preventing age-associated neuronal dysfunction, including that seen in age-related neurodegenerative disorders like AD.